In addition to causing tremendous obstetric and neonatal morbidity, pregnancy-associated malaria may have lasting consequences for the development of immunity during childhood. It has long been known that the fetal immune system is predisposed toward development of tolerance upon exposure to foreign antigens. The biological mechanisms underlying this process are only beginning to be understood, but recent data support a novel model of layered immune development, wherein the fetal immune system is populated during development by two distinct waves of lymphoid progenitor cells that differ in their intrinsic properties and developmental potential: fetal T cells (Tf), which are tolerogenic, and adult T cells (Ta), which are poised to mount effector responses. We propose to test this hypothesis by examining the consequences of in utero exposure to malaria antigens among infants born to women participating in two randomized trials of chemoprevention during pregnancy in a highly malaria-endemic region of Uganda. We hypothesize that fetal exposure to malaria antigens in utero can induce immune tolerance, which interferes with the later development of antimalarial immunity. We further hypothesize that infants with a Tf-skewed (predominantly tolerogenic) T cell compartment at birth will develop less robust Th1 responses and be slower to acquire natural immunity to malaria. In three aims, we will assess the relationship between in utero exposure to malaria antigens, the proportion of tolerogenic fetal T cells present at birth (Tf:Ta ratio), and the frequency and function of malaria-specific effector T cells and FoxP3+ regulatory CD4 T cells in cord blood, and we will determine how these factors influence the T cell response to postnatal infection and the incidence of clinical malaria during the first 3 years of life. By performing longitudinal assessments of mother-infant pairs who are followed closely from mid-gestation through early childhood and differ only in their prenatal exposure to malaria antigens, the proposed investigations will test a novel paradigm for understanding human fetal immune ontogeny and will define the immune consequences of prenatal exposure to malaria, as well the potential of chemoprevention during pregnancy to enhance antimalarial immunity during childhood.